Glutamate, the major excitatory neurotransmitter in the brain, elicits its effects by activating ligand-gated cation channels, termed ionotropic glutamate receptors (iGluRs), as well as metabotropic glutamate receptors (mGlu receptors). The latter belong to the G-Protein coupled receptor (GPCR) family 3 (Conn and Pin, Annu. Rev. Pharmacol. Toxicol. 37, 205-37, 1997) and are coupled through heterotrimeric G-proteins to intracellular effector systems. These receptor types exert multiple modulatory effects within the central nervous system (CNS). Eight mGlu receptor subtypes have been cloned from mammalian brain to date. Depending on their G-protein coupling profile, pharmacology and sequence identity, these receptors are classified into three groups (Conn and Pin, Annu. Rev. Pharmacol. Toxicol. 37, 205-37, 1997). Group I mGlu receptors primarily couple through Gq to increases in phosphoinositide hydrolysis and the cellular Ca2+-system via phospholipase C (PLC), and include the mGlu1 receptor and mGlu5 receptor. Group II mGlu receptors, which include mGlu2 and mGlu3, inhibit adenylylcyclase (AC), just as group III mGlu receptors, which comprise mGlu4, mGlu6, mGlu7 and mGlu8. Thereby, in groups II and III, the pertussis-toxin sensitive G-protein Gi is involved in signal transduction. However, group II and group III mGlu receptors differ in their sequence identity and pharmacological profile.
Of the 8 mGlu receptor subtypes various splice variants exist. Within group I mGlu receptors the splicing variability is most pronounced. MGlu1 exists in 6 different splicing forms. The receptors mGlu1a/a, 1b/b, 1c, 1d and 1f all differ in their C-terminal, intracellular domain (Prezeau et al., Mol. Pharmacol. 49, 422-429, 1996; Soloviev et al., Biochimica et Biophysica Acta 1446, 161-166, 1999), and mGlu1e is truncated N-terminally, lacking most of the protein coding region (Pin and Duvoisin, Neuropharmacol. 34, 1-26, 1995). So far of mGlu5 (group I), and the group III receptors mGlu4, mGlu7 and mGlu8 two splicing variants have been demonstrated. mGlu6 which is located solely in ON-bipolar cells of the retina (Nakanishi et al., Brain Res. Rev. 26, 230-235, 1998), only has one isoform. The same holds for mGlu2 and mGlu3 receptors (Fagni et al., TINS 23 (2), 80-88, 2000).
The synaptic localization of group I mGlu receptors and group II/III mGlu receptors differs. While group I receptors are located predominantly postsynaptically, group III mGlu receptors rather show a presynaptic localization (Shigemoto et al., J. Neurosci. 17, 7503-7522, 1997; Cartmell & Schoepp, J. Neurochem. 75(3), 889-907, 2000). Group II receptors seem to be located pre- and postsynaptically, depending on brain region and synapse-type. A perisynaptic localization of mGlu2 has also been demonstrated. In this case, the receptor might only be activated under high frequency stimulation, then preventing further transmitter release and thus reducing pathologically high levels of glutamate within the synaptic cleft. Autoreceptor function (medial perforant path, mossy fiber-CA3, spinal cord synapse, corticostriatal synapse) and heteroreceptor functions have been demonstrated for group II mGlu receptors at synapses in diverse brain regions. The pre- and perisynaptic localization of group II mGlu receptors, combined with their auto- and heteroreceptor function and their coupling to inhibitory intracellular signalling cascades implies an important role of this receptor type for the regulation of excitatory neurotransmission.
The first compounds which discriminated between the 3 different groups of mGlu receptors were low affinity agonists: 3,5-dihydroxyphenylglycine (3,4-DHPG), which selectively stimulates the group 1 mGlu receptors; (2R,4R)-4-aminopyrrolidine-carboxylic acid (2R,4R-APDC) activating group II mGlu receptors (Monn et al., J. Med. Chem. 39(15), 2990-3000, 1996) and L-Amino-4-phosphonobutyrate (L-AP4, Trombley and Westbrook, J. Neurosci. 12(6), 2043-50, 1992) for the activation of group III mGlu receptors. All these compounds have been valuable tools for the investigation of the various functions of mGlu receptors by in vitro studies, but none of these compounds has been shown to exert potent central effects after systemic administration. Other early compounds, which have mainly been used for in vitro studies, turned out to activate ionotropic glutamate receptors as well. For the widely used group II mGlu receptor agonist (2S, 1′R, 2′R, 3′R)-2-(2′,3′-dicarboxypropyl)glycine also activates NMDA receptors.
For studying the in vivo effects and therapeutic applications of group II agonists, the breakthrough came from the discovery of LY354740 and LY379268 (Formulae given e.g. in D. A. Barda et al., Bioorganic and Medicinal Chemistry Letters, 14, 3099-3102, 2004). These two compounds are highly specific group II receptor agonists with only very low affinity to other mGlu receptors or ionotropic glutamate receptors. They have EC50 values of 10 and 20 nM (LY354740) and 3 and 5 nM (LY379268), for mGlu2 and 3 respectively. While a differentiation between the two group II receptors is not possible, a specificity of >1:30.000 towards group I receptors and between 1:100 (mGlu6) to >1:30.000 (mGlu7) to group III receptors offers a high discrimination potential to these receptor types (Cartmell and Schoepp, J. Neurochem. 75(3), 889-907, 2000; Bräuner-Osborne et al., J. Med. Chem. 43 (14), 2609-2645, 2000). Both compounds were designed as conformationally constrained analogues of glutamate (Monn et al., J. Med. Chem. 40(4), 528-37, 1997; J. Med. Chem. 42(6), 1027-40, 1999), and represent competitive agonists at the glutamate binding site. Furthermore these two compounds are systemically active.
Derivatives of these compounds, MGS 0008 and MGS 0028 (Nakazato et al., J. Med. Chem. 43(25), 4893-909, 2000) and have a higher oral availability. They also show increased antagonistic effects on PCP-induced head-weaving and hyperactivity in rats. Recently also a highly selective antagonist for group II mGlu receptors has been identified (Kingston et al., Neuropharmacology 37(1), 1-12, 1998; Johnson et al., Neuropharmacology 38(10), 1519-29, 1999). No appreciable specific binding of the radio-ligand [3H]-LY341495 (formula given in D. A. Barda et al. 2004) was found in membranes of cells expressing human mGlu1a, mGlu5a, mGlu4a, mGlu6, or mGlu7a receptors. Many effects induced by group II receptor agonists could be reversed by this compound. Thus LY341495 also represents a highly selective tool compound.
Positive modulators activate the mGlu2 receptor dependent on the presence of glutamate (potentiators). Thus, the compound “sensitizes” the receptor to react already at lower concentrations of the ligand. Positive modulators can also activate the mGlu2 receptor directly. The mGlu receptors consist of a large extracellular N-terminal domain, which binds the natural ligand, glutamate, which is homologous to the periplasmatic amino acid binding proteins from bacteria. This domain is linked to a 7-transmembrane domain. This canonical domain, common to all G-protein coupled receptors, contains the canonical ligand binding site for GPCRs (compare rhodopsin in retinal). In the mGluRs this site is free and may play a role as modulatory site for positive and negative allosteric compounds.
A hint for the exact amino acid sites responsible for ligand binding of a model potentiator (LY487379, see Johnson et al., J. Med. Chem. 46(15), 3189-92, 2003) come from the amino acid comparison between mGlu2 receptor and mGluR3 in this region. As the potentiator is specific for mGlu2 receptor, the binding should not take place at mGluR3 and the responsible amino acids should be exactly the ones which differ between the two receptors. Recently the binding site of a model potentiator (LY487379) has been mapped by site directed mutagenesis. The binding site seems to be within the transmembrane domain of mGlu2 receptor (Schaffhauser et al., Mol. Pharmacol. 64(4), 798-810, 2003). In particular the amino acids 688, 689 and 735 are indicated for binding.
MGlu2 receptor is expressed in both separate and overlapping circuits of relevance for neuropsychiatric and neurological disorders. This includes expression in neocortex, thalamus, striatum, amygdala and hippocampus. Within these circuits mGlu2 receptor is mainly expressed presynaptically. As a consequence of this expression pattern it has been shown that excitatory transmitter release is regulated by group II agonists in diverse brain regions. For, it has been demonstrated that group II agonists normalize PCP-induced increase of glutamate in the prefrontal cortex (PFC) and that dopamine is regulated by group II agonists in a region-specific manner. As one function group II agonists increase dopamine and metabolites in the PFC. Also serotonin and metabolites are regulated in the PFC. This has further been demonstrated by a functional antagonism of 5-HT2A receptors in this brain region.
These data indicate that the mGlu2 receptor approach may normalize a number of de-regulated transmitters in schizophrenia. The mGlu2 receptor agonist/potentiator concept will likely give rise to the opportunity to normalize                positive symptoms, due to regulation of glutamate,        negative symptoms, due to regulation of dopamine and serotonin, and        cognitive symptoms, due to regulation of acetylcholine in the PFC.Besides schizophrenia, drug abuse may be an interesting disease indication, as group II agonists block of expression of locomotor sensitization by amphetamine, among a multitude of other described effects. The usefulness of such compounds is not limited to the disease states described above.        
The potentiator concept for mGlu2 receptor is relatively new (Barda et al., 2004), but necessary to evaluate the relevance of mGlu2 receptor versus mGluR3. This is of note, as the group II agonists described above do cross react with both receptor types. Within the recent years, reports directly demonstrate the relevance of mGlu2 receptor in psychosis models in rodents by describing function of mGlu2 receptor potentiators in models of PCP-induced hyperlocomotion, amphetamine-induced hyperlocomotion, and reversal of amphetamine-induced disruption of PPI in mice (Galici et al., JPET 315(3), 1181-1187, 2005).
Beyond these data, indicating a relevance of mGlu2 receptor potentiators in schizophrenia, new reports furthermore demonstrate efficacy of mGlu2 receptor potentiators in anxiety, as potentiators have been shown to be efficacious in rat fear-potentiated startle and stress-induced hyperthermia in mice (Johnson et al. Psychopharmacol, 179(1), 271-83, 2005).
A pure NMDA activation approach (the “glutamatergic hypothesis of schizophrenia”) may result in side effect liabilities. In particular excitotoxicity is a relevant side effect which needs to be considered early within a potential screening cascade of such projects. This side effect liability may limit the usefulness of such approaches.
As described above, the mGlu2 receptor positive modulator approach does not purely rely on the glutamatergic hypothesis, but likely is involved in the normalization of release of a number of excitatory neurotransmitters. Consequently, to date there is no evidence for excitotoxic liability of group II agonists or mGlu2 receptor positive modulators. Group II agonists even show the opposite effects. They are neuroprotective in the MPTP model of Parkinson's disease, they reduce low Mg2+-induced epileptiform discharges in slice preparations and they have anticonvulsant action in acute seizure models.
As a relevant side effect, a negative influence on cognition was described for group II agonists (Higgins et al., Neuropharmacol 46, 907-917, 2004). However, to date this finding is controversial in the literature. While one group finds a reversal of cognitive deficits induced by PCP (Moghaddam and Adams, Science 281(5381), 1349-52, 1998), a second group finds a reduction of DNMTP performance with the mGlu2 receptor agonist LY354740, which is not present in mGlu2 receptor knockout mice (Higgins et al., Neuropharmacol. 46, 907-917, 2004). This finding contrasts to the data from Moghaddam and Adams and would also contradict the normalization of ACh release in the PFC by this compound (see above).
WO 2006/015158 and WO 2006/047237 describe heterocyclic compounds carrying an indanone moiety, the compounds being potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.
WO 2006/030032 describes pyridinone compounds which are potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.
WO 2006/049969 describes N-(phenyl)aminoalkyl substituted pyrimidine compounds, which are potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.
WO 2006/057860, WO 2006/057869 and WO 2006/057870 describe compounds carrying a 4-acyl-3-hydroxy-phenyl moiety. The compounds are suggested to be potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.
WO 2006/091496 describes compounds carrying a benzazole moiety, the compounds being suggested as potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.
WO 2006/020879, WO2007/021308 and WO 2007/021309 disclose isoindolone compounds, which are suggested as potentiators of metabotropic glutamate receptors, including the mGlu2 receptor.
WO 2008/145616 discloses heterocyclic compounds which are positive modulators of metabotropic receptors, including the mGlu2 receptor.
WO 2008/130853 discloses heterocyclic hydrazides and their use as metabotropic glutamate receptor potentiators.
Although the compounds of prior art have a high affinity with regard to the mGlu2 receptor, their receptor binding profile and/or their pharmacological profile is not always satisfactory. In particular, the compounds often have poor selectivity with regard to mGlu2 receptor in comparison with mGlu3 or group III mGlu receptors or are glutamate agonists. Moreover, the potentiators are in terms of (i) binding affinity, (ii) receptor potentiation and/or stimulation profile, (iii) selectivity versus other receptors, (iv) physicochemical properties, (v) in vitro microsomal stability and (vi) pharmacokinetic parameters suboptimal.
It is an object of the present invention to provide further compounds which are potentiators of metabotropic glutamate receptors, in particular of the mGlu2 receptor, and which thus are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. In particular, such diseases are central nervous system disorders selected from the group of schizophrenia, drug abuse, anxiety, migraine, depression and epilepsy and the like.
These and further objects are solved by the compounds of the general formula I, as described herein, as well as by the N-oxides thereof, and by their pharmaceutically acceptable salts.